The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells

Chih Wei Chen, Ning Tsao, Lin Yi Huang, Yun Yen, Xiyong Liu, Christine Lehman, Yuh Hwa Wang, Mei Chun Tseng, Yu Ju Chen, Yi Chi Ho, Chian Feng Chen, Zee Fen Chang

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients. Furthermore, overexpression of R2 in non-tumorigenic cells progressively increases genome stress, promoting transformation. These cells display alterations in replication fork progression, elevated genomic uracil, and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase abolishes R2-induced genome instability. Thus, the expression level of dUTPase determines the role of high R2 in driving genome instability in cancer cells.

Original languageEnglish
Pages (from-to)1287-1299
Number of pages13
JournalCell Reports
Volume16
Issue number5
DOIs
Publication statusPublished - Aug 2 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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